Immune reconstitution after allogenic stem cell transplantation: An observational study in pediatric patients

Abstract Introduction The immune reconstitution (IR) after the allogenic hematopoietic stem cell transplantation (allo-HSCT) is a progressive process intrinsically correlated to the therapeutic success. It is essential to understand the interfering factors in IR to prevent the HSCT-related mortality. Methods We retrospectively evaluated the clinical outcomes, absolute lymphocyte counts (ALCs) and lymphocyte subtypes at different time-points of 111 pediatric patients with allogeneic HSCT for malignant and non-malignant diseases from 2013 to 2018. Results The ALCs gradually increased on D+30, D+100, and D+180 (medians 634/μL, 1022/μL and 1541/μL, respectively). On D+100, the CD3+CD8+ achieved the highest recovery rate (68%), followed by the CD16+CD56+ (47%), CD3+CD4+ (39%) and CD19+ (8%). The adequate ALC recovery was associated with age < 8 years, bone marrow grafts, myeloablative conditioning, non-use of serotherapy and non-haploidentical donors. The ALC and CD3+CD8+ on D+100 counts were higher in patients with the cytomegalovirus infection. The CD3+CD4+ recovery was associated with an age < 8 years, a non-malignant disease and a lower incidence of acute graft-versus-host disease ≥ grade 2. Furthermore, the ALC recovery on D+100 resulted in a higher overall survival, regardless of the disease type (HR 3.65, 1.05 - 12.71, p= 0.04). Conclusion Several factors influenced the IR after the allo-HSCT. The ALC ≥ 500/μL on D+100 was a simple IR predictor of survival, easily available to resource-limited centers.

Saprochaete clavata invasive infection: characterization, antifungal susceptibility, and biofilm evaluation of a rare yeast isolated in Brazil

ABSTRACT Rare emerging pathogens such as Saprochaete clavata are associated with invasive fungal diseases, high morbidity, mortality, rapidly fatal infections, and outbreaks. However, little is known about S. clavata infections, epidemiology, risk factors, treatment, biofilms, and disease outcomes. The objective of this study was to describe a new case of severe S. clavata infection in a patient diagnosed at a referral children's hospital in Brazil, including antifungal minimal inhibitory concentration, S. clavata biofilm characterization, and molecular characterization. The S. clavata isolated from an immunocompromised 11-year-old male patient was characterized using MALDI-TOF, Gram staining, scanning electron microscopy (SEM), and next generation sequencing (NGS) of genomic DNA. Biofilm production was also evaluated in parallel with determining minimal inhibitory concentration (MIC) and biofilm sensitivity to antifungal treatment. We observed small to medium, whitish, farinose, dry, filamentous margin colonies, yeast-like cells with bacillary features, and biofilm formation. The MALDI-TOF system yielded a score of ≥ 2,000, while NGS confirmed S. clavata presence at the nucleotide level. The MIC values (in mg L-1) for tested drugs were as follows: fluconazole = 2, voriconazole ≤ 2, caspofungin ≥ 8, micafungin = 2, amphotericin B = 4, flucytosine ≤ 1, and anidulafungin = 1. Amphotericin B can be active against S. clavata biofilm and the fungus can be susceptible to new azoles. These findings were helpful for understanding the development of novel treatments for S. clavata-induced disease, including combined therapy for biofilm-associated infections.

Risk of acute kidney injury and cost-effectiveness analysis comparing vancomycin and linezolid for the treatment of pediatric patients infected with Gram-positive bacteria / Risco de lesão renal aguda e custo-efetividade comparando vancomicina e linezolida para o tratamento de pacientes pediátricos infectados por bactérias Gram-positivas

Objective: This study aimed to compare the occurrence of acute kidney injury (AKI) in pediatric patients who used vancomycin (VAN) or linezolid (LNZ) to treat Gram-positive coccus (GPC) infections and to assess which treatment (VAN or LNZ) is the most cost-effective considering a pediatric hospital perspective. Methods: A retrospective cohort was performed to evaluate the occurrence of nephrotoxicity in pediatric patients without previous AKI, with GPC infections that used LNZ, or VAN monitored by serum VAN levels. Initially, descriptive analysis and Fisher and chisquare test were performed for this comparison. Then, a cost-effectiveness analysis was conducted through a decision tree model. The outcomes of interest were the rate of AKI related to the drug and the rate of admission to the intensive care unit (ICU) and cure. Results: In patients without previous acute kidney injury (AKI), 20% developed nephrotoxicity associated with VAN versus 9.6% in the LNZ group (p = 0.241). As there was no difference in nephrotoxicity between VAN andlinezolid (LNZ), vancomycin (VAN) monitored by serum VAN levels can optimize and rationalize the treatment. The nephrotoxicity risk criterion should not guide the prescription for LNZ. Furthermore, the average global cost of treatment with VAN was approximately R$ 43,000, while for LNZ, it was R$ 71,000. Conclusion: VAN was considered dominant (lower cost and greater effectiveness) over LNZ for treating patients with GPC infection.

Objetivo: Este estudo objetivou comparar a ocorrência de lesão renal aguda (LRA) em pacientes pediátricos que usaram vancomicina (VAN) ou linezolida (LNZ) para tratar infecções por cocos Gram-positivos (CGP) e avaliar qual tratamento (VAN ou LNZ) é o mais custo-efetivo considerando a perspectiva de um hospital pediátrico. Métodos: Foi realizada uma coorte retrospectiva para avaliar a ocorrência de nefrotoxicidade em pacientes pediátricos sem LRA prévia, com infecções por CGP que utilizaram LNZ ou VAN, combinada com vancocinemia. Para essa comparação, inicialmente foram realizados análise descritiva e testes de Fisher e qui-quadrado. Em seguida, foi realizada uma análise de custo-efetividade por meio de um modelo de árvore de decisão. Os desfechos de interesse foram a taxa de LRA relacionada ao medicamento e a taxa de internação em unidade de terapia intensiva e cura. Resultados: Nos pacientes sem LRA prévia, 20% deles desenvolveram nefrotoxicidade associada à VAN versus 9,6% no grupo LNZ (p = 0,241). Como não houve diferença na nefrotoxicidade entre VAN e LNZ, a VAN combinada com a vancocinemia pode otimizar e racionalizar o tratamento, e a prescrição de LNZ não deve ser guiada pelo critério de risco de nefrotoxicidade. Além disso, o custo médio global do tratamento com VAN foi de aproximadamente R$ 43.000, enquanto para LNZ foi de R$ 71.000. Conclusão: Assim, a VAN foi considerada dominante (menor custo e maior eficácia) sobre a LNZ para o tratamento de pacientes com infecção por CGP.

From disease to noninvasive intracranial monitoring / Da doença ao monitoramento intracraniano não invasivo

ABSTRACT Professor Sérgio Mascarenhas was a Brazilian researcher with a vast legacy. His work paved the way for new research possibilities by consolidating the use of innovation and transdisciplinary science. In Medicine, he proposed changes to what had previously been well-accepted concepts, and his contributions have influenced medical practices. Although many authors consider intracranial pressure (ICP) as an unrivaled variable for monitoring and diagnosis of many diseases, its clinical applicability is still the subject of debate in the literature because of the difficulty in standardizing protocols. Mascarenhas's research and the creation of a device for noninvasive monitoring of intracranial compliance are discussed and are shown to have led to the creation of Brain4care, a start-up, and a new perspective on the debate on ICP monitoring.

RESUMO O professor Sérgio Mascarenhas foi um pesquisador com vasto legado. Seu trabalho abriu caminho para novas possibilidades de pesquisa, consolidando o uso da inovação e da ciência transdisciplinar. Na Medicina, ele propôs mudanças no que antes eram conceitos bem-aceitos, e suas contribuições influenciaram a prática médica. Embora muitos autores considerem a pressão intracraniana (PIC) uma variável incomparável para o monitoramento e o diagnóstico de uma série de doenças, sua aplicabilidade clínica ainda é motivo de debate na literatura pela dificuldade de padronização de protocolos. A pesquisa do Professor Mascarenhas e a criação de um dispositivo para o monitoramento não invasivo da complacência intracraniana levaram à criação do Brain4care, uma start-up, e a uma nova perspectiva sobre o debate do monitoramento da PIC.

PRAT tool: a harmonization of antimicrobial stewardship program interventions

Objective: The Antimicrobial Stewardship Program (ASP) in hospitals aims to promote the rational use of antimicrobials, providing better results to patients (increasing effectiveness and decreasing the risk of adverse events), hospital epidemiology (impact on levels of microbial resistance), and enable cost-effectiveness studies. Therefore, a tool (called PRAT­ antimicrobial therapy-related problem) is suggested in this paper. This unvalidated tool is the initial step towards organizing the antimicrobial therapy-related interventions to improve the use of this drug class, mainly by suggesting a harmonized registry process of ASP interventions. Methods: Therefore, this work presents the PRAT tool, developed based on the 10 years' experience of ASP at Pequeno Príncipe Hospital, inspired by the classification for drug-related problems of the Pharmaceutical Care Network Europe and according to a collaborative work using the Delphi technique. Results: This tool allows the identification and exact description of the antimicrobial therapy-related problem in 17 domains and 67 subcategories. Based on this identification, it suggests how to classify this problem (effectiveness, safety and need/indication) and what interventions can be conducted. Conclusion: This tool has the potential to establish a profile of antimicrobial-related problems, allowing prioritization to be visualized through the most (and least) interventions made in a given period, and might be useful in improving the quality of care through settings, by means of targeted educational interventions. Furthermore, if there is a harmonization of terminology for the classification of antimicrobial therapy-related problems, other hospitals can adopt it, and so the tool can improve research and comparison between institutions (benchmarking).

COVID-19 associated multisystem inflammatory syndrome in children mimicking acute appendicitis - how to differentiate and conduct pediatric patients during the pandemic? - Proposal of a management flowchart / Síndrome inflamatória multissistêmica em crianças associada ao COVID-19 mimetizando apendicite aguda - como diferenciar e conduzir pacientes pediátricos durante a pandemia? - Proposta de fluxograma de atendimento

ABSTRACT Introduction: the new coronavirus pandemic has been a reality throughout 2020, and it has brought great challenges. The virus predominantly manifests in the pediatric population with mild symptoms. However, an increase in the incidence of Multisystemic Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 has been described in the literature. MIS-C manifests mainly with fever and gastrointestinal symptoms and may mimic acute abdomen due to acute appendicitis. The objective of this study is to propose a care flowchart for suspected cases of acute appendicitis in the initial phase in pandemic times, considering the possibility of MIS-C. This situation was brought up by a patient treated in a pediatric hospital in Brazil. Discussion: It was possible to identify common signs and symptoms in the reported patient and those published cases that may serve as alerts for early identification of MIS-C cases. Based on the literature review and on the similarities between the syndrome and the inflammatory acute abdomen in children, we elaborated an initial approach for these cases to facilitate the identification, early diagnosis, and management. The flowchart considers details of the clinical history, physical examination, and complementary exams prior to the indication of appendectomy in patients with initial phase symptoms. Conclusion: MIS-C, although rare and of poorly known pathophysiology, is most often severe and has a high mortality risk. The use of the proposed flowchart can help in the diagnosis and early treatment of MIS-C.

RESUMO Introdução: a pandemia do novo coronavírus arrastou-se ao longo de 2020 e trouxe grandes desafios. Acredita-se que o vírus manifesta-se na população pediátrica predominantemente com quadros leves, entretanto, aumento da incidência da Síndrome Inflamatória Multissistêmica em Crianças (SIM-C) associada à COVID-19 tem sido descrito na literatura. A SIM-C manifesta-se principalmente com febre e sintomas gastrointestinais, podendo mimetizar abdome agudo inflamatório por apendicite aguda. O objetivo deste trabalho é propor fluxograma de atendimento dos casos suspeitos de apendicite aguda em fase inicial, em tempos de pandemia, considerando-se a possibilidade de SIM-C, motivado pelo caso de paciente atendido em hospital pediátrico no Brasil. Discussão: Foi possível identificar sinais e sintomas em comum entre o paciente aqui relatado e casos publicados que podem servir de alerta para identificação precoce dos casos de SIM-C. Com base na revisão da literatura e nas semelhanças entre a síndrome e quadros de abdome agudo inflamatório na criança, foi elaborado fluxograma de abordagem inicial destes doentes para facilitar a identificação, diagnóstico precoce e condução dos pacientes. O fluxograma leva em consideração detalhes da história clínica, exame físico e exames complementares antes da indicação de apendicectomia em pacientes com sintomas na fase inicial. Conclusão: A SIM-C, apesar de rara e da fisiopatologia pouco conhecida, apresenta-se na maioria das vezes de forma grave e possui alto risco de mortalidade. O uso do fluxograma proposto pode auxiliar no diagnóstico e tratamento precoce da SIM-C.

Risk factors for candidemia mortality in hospitalized children / Fatores de risco de mortalidade por candidemia em crianças internadas

Abstract Objective: To evaluate risk factors associated with death due to bloodstream infection caused by Candida spp. in pediatric patients and evaluate the resistance to the main anti-fungal used in clinical practice. Methods: This is a cross-sectional, observational, analytical study with retrospective collection that included 65 hospitalized pediatric patients with bloodstream infection by Candida spp. A univariate analysis was performed to estimate the association between the characteristics of the candidemia patients and death. Results: The incidence of candidemia was 0.23 cases per 1000 patients/day, with a mortality rate of 32% (n = 21). Clinical outcomes such as sepsis and septic shock (p = 0.001), comorbidities such as acute renal insufficiency (p = 0.01), and risks such as mechanical ventilation (p = 0.02) and dialysis (p = 0.03) are associated with increased mortality in pediatric patients. The resistance and dose-dependent susceptibility rates against fluconazole were 4.2% and 2.1%, respectively. No resistance to amphotericin B and echinocandin was identified. Conclusion: Data from this study suggest that sepsis and septic shock, acute renal insufficiency, and risks like mechanical ventilation and dialysis are associated with increased mortality in pediatric patients. The mortality among patients with candidemia is high, and there is no species difference in mortality rates. Regarding the resistance rates, it is important to emphasize the presence of low resistance in this series.

Resumo Objetivo: Avaliar os fatores de risco associados ao óbito por infecção da corrente sanguínea causada pela Candida spp em pacientes pediátricos e avaliar a resistência ao principal antifúngico usado na prática clínica. Métodos: Este é um estudo transversal, observacional e analítico com coleta retrospectiva que incluiu 65 pacientes pediátricos internados com infecção da corrente sanguínea por Candida spp. Foi feita uma análise univariada para estimar a associação entre as características dos pacientes com candidemia e o óbito. Resultados: A incidência de candidemia foi de 0,23 casos em cada 1.000 pacientes/dia, com taxa de mortalidade de 32% (n = 21). O resultado clínico como sepse e choque séptico (p = 0,001), comorbidades como insuficiência renal aguda (p = 0,01) e riscos como ventilação mecânica (p = 0,02) e diálise (p = 0,03) estão associados ao aumento da mortalidade em pacientes pediátricos. As taxas de resistência e susceptibilidade dose-dependente contra o fluconazol foram de 4,2% e 2,1%, respectivamente. Não foi identificada resistência à anfotericina B e equinocandina. Conclusão: Os dados de nosso estudo sugerem que a sepse e o choque séptico, a insuficiência renal aguda e riscos como ventilação mecânica e diálise estão associados ao aumento da mortalidade em pacientes pediátricos. A mortalidade entre pacientes com candidemia é alta e não há diferença nas taxas de mortalidade entre as espécies. Sobre a resistência, é importante enfatizar a presença de baixa resistência nesta série.